Doxycycline and Cancer Stem Cell Inhibition

Updated: Jun 1


Recently a patient asked me about the potential use of antibiotics for killing cancer cells.  It was not a completely outlandish question, as several antibiotics have been shown to inhibit cancer growth or increase a cancer’s sensitivity to treatments.  It’s also not uncommon for drugs to have multiple actions quite different from their first intended use. “Drug repurposing” is currently a hot topic in medicine.  And, it’s always a good idea to take your patient inquiries seriously.  This time the question was particularly interesting as it had to do with eliminating cancer stem cells.


Cancer stem cells (CSCs) are hard to hit targets.  These cells are typically the cancer cells that remain in the body after a person has completed cancer treatment.  CSC’s are considered to the cause for tumor recurrence, cancer progression, treatment resistance, and the development of distant metastasis in most cancer types.  As such, therapies that can target and eliminate CSCs are sorely needed.


Cancer stem cells are able to promote cancer growth and recurrence because they monitor the internal environment of the body.  By monitoring the environment inside the body, the CSCs can identify both resources and threats to enhance their chances of survival.  These abilities are often referred to as “stemness.”


Recently, it has been determined that CSCs have some additional interesting properties.  The CSC’s have a high mitochondrial mass.  Mitochondrial mass is a term used to describe the quantity of mitochondria inside of a cell.  Mitochondria are small membrane-bound organelles that are responsible for producing cellular energy, ie. the energy that cells use to function.  Mitochondria are an interesting addition to our cells, as they are not of human origin.  Mitochondria are actually evolved from bacteria and millions of years ago they moved into our distant ancestor’s cells.  More on this coming up.


The high mitochondrial mass of CSCs is a surrogate marker for mitochondrial biogenesis and mitochondrial protein translation. These terms basically describe the functioning of the mitochondria.  Increased biogenesis and protein translation equate to busy mitochondria.  Several recent studies have found that CSCs with high mitochondrial mass have more ability to spread to other parts of the body, the strongest tumor initiating activity, and higher proliferation potential.  CSCs with high mitochondrial mass have also been found to have elevated levels of an enzyme named telomerase reverse transcriptase.  Activation and mutations of this enzyme are associated with cancer aggressiveness and cancer cell replication immortality.  None of these things are good.


Several pieces of medical research have been published suggesting that there may be a way destroy CSCs by targeting their high mitochondrial mass.  Because mitochondria evolved from bacteria, they retain some similarities with their ancestors.  These retained similarities make mitochondria sensitive to certain antibiotics.  It turns out that several classes of FDA approved antibiotics can inhibit mitochondrial biogenesis via their action on mitochondrial ribosomes. What this means is that the antibiotics can inhibit the CSCs from using their mitochondria.  Without the ability to use their increased number of mitochondria, the CSC’s die.


Indeed, some antibiotics do seem to have the ability to kill cancer stem cells. This research (https://www.oncotarget.com/article/3174/text/) reported that antibiotics were able to eradicate CSCs from 12 cancer lines from 8 different types of cancer.  The cancer types included breast, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma.

Additional research (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194352/) reported that when doxycycline, a tetracycline antibiotic, was administered to breast cancer patients interesting things happened.  The study looked at cell-based markers of stemness, namely CD44 and ALDH1, among others.  Samples were taken from patients prior to surgery and then doxycycline was given orally for two weeks.  The patients then had their markers re-drawn and then compared to their prior results and also to a group of control patients who had not received doxycycline. Analysis of the markers showed that markers of stemness (CD44) reduced between 17.65 and 66.67% in 8 out of 9 patients.  In two patients with HER2 positive breast cancer ALDH1 levels- the other stemness marker- decreased nearly 60% in one patient and 90% in the other.


Despite these encouraging results, there does seem to be a way in which CSCs can become resistant to the anti-cancer action of doxycycline.  To become resistant to doxycycline the CSCs change their energy producing pathways.  Cancer cells can typically produce energy through multiple mechanisms.  To become resistant to doxycycline CSCs are limited to a single energy producing pathway known as glycolysis.  This dependence on a single energy depending pathway can render the CSCs vulnerable to glycolysis inhibitors. (ie. things that prevent CSCs from making energy.) In nature, a deficit of energy typically results in death; it’s called starvation.


Within the integrative medicine filed there are a number of substances which are used as glycolysis inhibitors. It turns out that one particular substance which has a long history of use by integrative cancer practitioners can also be used to inhibit glycolysis.  That substance is vitamin C.  High doses of vitamin C are often given by IV to people fighting cancer as evidence shows that it can kill cancer cells, boost the immune system, and increase quality of life.  High doses of IV vitamin C generates free radicals that destroy cancer cells.  Now, it seems that vitamin C can potentially also be used in combination with doxycycline (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620172/) to eradicate CSCs by blocking glycolysis.


It is important to point out that research on the use of antibiotics combined with vitamin C to kill cancer stem cells is still new.  However, both substances have been used in medicine for many years and both have proven track records of safety.  The data reviewed here is very exciting in that it may help to prevent the progression and recurrence of several types of cancer.  This includes cancers like triple negative breast cancer and ovarian cancers, which typically have a high recurrence rates. As interesting as this research is, please discuss these things with a qualified physician before starting any new treatments or therapies.

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